tbuckley/cabot-search huggingface dataset:
Camrelizumab combined with SOX in the first-line treatment of unresectable advanced or metastatic gastric/gastroesophageal junction (G/GEJ) adenocarcinoma: A single-arm, prospective, and open-label clinical study.
Authors: Wenlou Liu, Xiaobing Qin, Yang Zhao, Yan Ge, Juanjuan Tang, Hongmei Wang, Zhengxiang Han
Journal: Journal of Clinical Oncology (2022)

e16090 Background: First-line chemotherapy for advanced human epidermal growth factor receptor 2 (HER2)-negative gastric/gastroesophageal junction (G/GEJ) adenocarcinoma results in median overall survival (mOS) &lt; 1 year. The programmed death (PD)-1 inhibitor provided superior OS in advanced G/GEJ adenocarcinoma combind with chemotherapy. However, the continuous explore about PD-1 inhibitors of first-line treatment with G/GEJ adenocarcinoma patients is promising. Camrelizumab, an anti-PD-1 monoclonal antibody, has been shown to have synergistic antitumor effects in the treatment of G/GEJ adenocarcinoma patients. We aimed to evaluate the safety and efficacy of camrelizumab combined with SOX in the first-line treatment of advanced G/GEJ adenocarcinoma. Methods: In this study (ChiCTR2000029691), eligible patients were diagnosed as unresectable advanced, postoperative recurrent ormetastatic, HER2-negative G/GEJ adenocarcinoma, and treatment-naive with chemotherapy, VEGFR2 inhibitors or PD-1/PD-L1 inhibitors. Patients received camrelizumab (200 mg, I.V., d1) and SOX regimen (oxaliplatin, 130 mg/m 2 , d1; S-1, 20mg/m 2 , bid, d1-14) every 3 weeks, until disease progression, intolerable toxicities, or physician/patient withdrawal. The safety and efficacy were assessed by investigators per CTCAE v5.0 and RECIST v1.1, respectively. The primary endpoint was progress free survival (PFS), and the secondary endpoints were overall survival (OS), objective response rate (ORR), and disease control rate (DCR). Results: From March 30, 2020 to March 18, 2021, 27 patients had been enrolled to receive therpy with camrelizumab and SOX regimen. The patients were characterized with a median age of 60 years (range 26-79), 88.9% males and 11.1% females, 40.7% GEJ adenocarcinoma, 88.9% lymph node metastasis, 25.9% liver metastases, and 18.5% of patients had a history of tumor-related surgery. As of Nov 2, 2021, with a median follow-up of 8.8 months (range, 0.9-16.8), safety and efficacy were assessed in 20 evaluable patients, with overall response of 8 partial response (PR) and 9 stable disease (SD). Confirmed ORR and DCR were 40.0% (95% CI, 20.0%-63.6%) and 85.0% (95% CI, 61.1%-96.0%), respectively. The median PFS and OS were 12.7 months (95% CI, 4.9-20.5) and 16.8 months (95% CI, 3.5-30.0), respectively. Grade 3-4 treatment-related adverse events occurred in 18.5% of patients, with anemia and neutropenia ranking the most frequent. No new safety signals was identified. Conclusions: Camrelizumab combined with SOX was well tolerated and demonstrated encouraging efficacy for previously untreated with chemotherapy, VEGFR2 inhibitors or PD-1/PD-L1 inhibitors, unresectable advanced or metastatic, HER2-negative G/GEJ adenocarcinoma. Clinical trial information: ChiCTR2000029691.
PATH-02. Using DNA methylation profiling to define tumor type and appropriate treatment: a case report and review of the literature of a rare CNS CIC altered sarcoma
Authors: William Brodwater, Yelena Wilson, Alexis Judd, Sarah Rush, Erin Wright
Journal: Neuro-Oncology (2022)

Abstract The utilization of methylation profiling is increasingly becoming part of the standard evaluation for high-grade malignancies. CNS primary tumors with CIC alteration are a recently recognized CNS tumor entity identified via DNA methylation profiling of primitive neuroectodermal tumors (PNET). PNETs have historically carried a poor overall prognosis; however, CNS tumors with CIC alteration have rarely been described in the literature and much remains to be discovered regarding the presentation, tumor characteristics, outcomes, and ideal treatment strategy to optimize survival in these patients. We describe the case of a 2-year-old Hispanic female with a CNS primary tumor with CIC alteration. This patient initially presented with a five-week history of fatigue, headaches, emesis, and right-sided muscle weakness and was found to have a right-sided supratentorial mixed solid and cystic mass. The initial diagnosis was consistent with a high-grade neuro-epithelial tumor based on histology and standard CNS tumor genetic markers. Due to poorly defined tumor characteristics, a sample was also sent for DNA methylation profiling. The profiling pattern was consistent with a CNS CIC altered sarcoma thereby significantly altering the treatment plan. Accurate diagnosis is critical in managing patients with cancer. DNA methylation profiling has contributed to diagnostic accuracy in these aggressive tumors; however, it also creates challenges with beginning treatment expediently due to the time required for processing and interpretation. This case illustrates the positive utility of DNA methylation to better characterize tumor types and the impact this has on both treatment as well as prognosis.
IMG-07. Contralateral transient contrast enhancement in a patient with IDH1wt MGMT promoter-methylated GBM responding to TMZ and individualized multimodal immunotherapy
Authors: Andrii Matiashchuk, Jennifer Makalowski, Michael Bitar, Peter Van de Vliet, Wilfried Stuecker, Stefaan Van Gool
Journal: Neuro-Oncology (2022)

Abstract Immunotherapy-induced MRI changes remain challenging when treating GBM patients with immunotherapy as part of a combined treatment. The iRANO criteria provide a decision-tree in order to avoid over- and under-treatment reactions when contrast-enhancing lesions become visible and should be interpreted. We report a 34-year female, 34 weeks pregnant, who presented with epilepsy, and was diagnosed with IDH1wt MGMT promoter-methylated GBM after biopsy. On MRI, the left occipital lesion was mostly cystic-necrotic with peripheral contrast enhancement, and crossed over the corpus callosum to the right. The volume was calculated as 64 cm³ (abc/2 formula). She was treated with radiochemotherapy and 12 TMZm cycles. Within each TMZ cycle 5 days of immunogenic cell death (ICD) therapy (5 injections with Newcastle Disease Virus and 5 sessions of modulated electrohyperthermia (Oncotherm 50 min 40-60 Watt) was added at days 8 to 12. After all chemo-/ICD-therapy we continued with active specific immunotherapy: two autologous mature monocyte-derived dendritic cell vaccines loaded with ICD therapy-induced serum-derived antigenic extracellular microvesicles and apoptotic bodies (IO-Vac®). One month after the second IO-Vac®, 17 months after diagnosis, a temporal right FLAIR-visible region showed expansion, and three months later also diffuse contrast enhancement, which was confirmed in a control scan one month later. The original tumor was meanwhile reduced to 16 cm³. However, in the last available scan, two months after the former, the contrast enhancement was disappeared, and the pathologic area on FLAIR was diminished. The original tumor size was reduced to 2 cm³, two year after first diagnosis. She showed allergic skin reactions to TMZ, which was covered with systemic histamine intake. There were no side effects related to multimodal immunotherapy. Transient MRI changes can be observed even in distance from the original tumor and can be interpreted as immune-mediated effects when the original tumor is responding.
Sutimlimab in patients with cold agglutinin disease: results of the randomized placebo-controlled phase 3 CADENZA trial
Authors: Alexander Röth, Sigbjørn Berentsen, Wilma Barcellini, Shirley D’Sa, Bernd Jilma, Marc Michel, Ilene C. Weitz, Masaki Yamaguchi, Jun-ichi Nishimura, Josephine M. I. Vos, Michael Storek, Nancy Wong, Parija Patel, Xiaoyu Jiang, Deepthi S. Vagge, Marek Wardęcki, Frank Shafer, Michelle Lee, Catherine M. Broome
Journal: Blood (2022)

Sutimlimab, a first-in-class humanized immunoglobulin G4 (IgG4) monoclonal antibody that selectively inhibits the classical complement pathway at C1s, rapidly halted hemolysis in the single-arm CARDINAL study in recently transfused patients with cold agglutinin disease (CAD). CADENZA was a 26-week randomized, placebo-controlled phase 3 study to assess safety and efficacy of sutimlimab in patients with CAD without recent (within 6 months prior to enrollment) transfusion history. Forty-two patients with screening hemoglobin ≤10 g/dL, elevated bilirubin, and ≥1 CAD symptom received sutimlimab (n = 22) or placebo (n = 20) on days 0 and 7 and then biweekly. Composite primary endpoint criteria (hemoglobin increase ≥1.5 g/dL at treatment assessment timepoint [mean of weeks 23, 25, 26], avoidance of transfusion, and study-prohibited CAD therapy [weeks 5-26]) were met by 16 patients (73%) on sutimlimab, and 3 patients (15%) on placebo (odds ratio, 15.9 [95% confidence interval, 2.9, 88.0; P < .001]). Sutimlimab, but not placebo, significantly increased mean hemoglobin and FACIT-Fatigue scores at treatment assessment timepoint. Sutimlimab normalized mean bilirubin by week 1. Improvements correlated with near-complete inhibition of the classical complement pathway (2.3% mean activity at week 1) and C4 normalization. Twenty-one (96%) sutimlimab patients and 20 (100%) placebo patients experienced ≥1 treatment-emergent adverse event. Headache, hypertension, rhinitis, Raynaud phenomenon, and acrocyanosis were more frequent with sutimlimab vs placebo, with a difference of ≥3 patients between groups. Three sutimlimab patients discontinued owing to adverse events; no placebo patients discontinued. These data demonstrate that sutimlimab has potential to be an important advancement in the treatment of CAD. This trial was registered at www.clinicaltrials.gov as #NCT03347422.
DIPG-30. A Phase 1, Safety and Dose Escalation Study of BXQ-350 in Combination with Radiation in Pediatric Patients with Diffuse Midline Glioma or Diffuse Intrinsic Pontine Glioma
Authors: Kathleen McCarthy O'Toole Dorris, Maryam Fouladi, Trent Hummel, Ray Takigiku, Gilles Tapolsky, Richard Curry III
Journal: Neuro-Oncology (2022)

Abstract The significance of sphingolipid metabolism in brain cancers has been demonstrated and enzymes involved in sphingolipid metabolism are being investigated as novel therapeutic targets for adult and pediatric brain cancers. Saposin C is a human protein encoded by the Psap gene and is an allosteric activator of enzymes involved in sphingolipid/ceramide metabolism. BXQ-350 is a nanovesicle of Saposin C that has broad anticancer activity, inducing apoptosis of cancer cells and an anti-tumoral immune response by lowering Sphingosine-1-Phosphate and increasing ceramides concentrations. Also, BXQ-350 is synergistic with radiation therapy. BXQ-350 was investigated in a Phase 1 dose-escalation safety study in pediatric brain cancer patients (NCT03967093); results showed that it was well-tolerated, a MTD was not established, and the safety profile warranted the investigation of combination studies at the highest dose tested (3.4 mg/kg). Additionally, results from a Phase 1 safety and dose escalation study in adult patients with advanced solid malignancies (NCT02859857) indicated that BXQ-350 was well tolerated and showed single agent activity with evidence of modulating sphingolipid metabolism and impacting the immune system positively. The primary objective of this dose-escalation study is to describe the safety profile and to determine the maximum tolerated dose of BXQ-350 in combination with radiation. BXQ-350 is administered intravenously in a modified Fibonacci cohort-based dose escalation design starting at 2.4mg/kg. Multiple secondary parameters are included to characterize BXQ-350’s pharmacokinetic parameters, efficacy profile and investigate potential biomarkers. This trial is currently enrolling at 3 US sites; as of January 2022, enrollment of cohort 1 (2.4 mg/kg and 54 Gy) has been completed while enrollment in cohort 2 (3.2 mg/kg and 54 Gy) is on-going. To this date, no dose-limiting toxicity has been observed and the combination BXQ-350 plus radiation has been well tolerated. Current results will be presented.
Efficacy of immunotherapy and sequencing of checkpoint inhibition for metastatic ocular melanoma.
Authors: Anuja Abhyankar, Satish Maharaj, Donald M. Miller
Journal: Journal of Clinical Oncology (2022)

e21526 Background: Ocular melanoma (OM) is the most common intraocular tumor in adults. However, it is still rare as compared to other subtypes of melanoma. Treatment of primary OM is certainly successful, but most therapies assessed in treatment of metastatic OM have not shown promise. Immunotherapy (IO), which has otherwise held prospect for durable remissions in other metastatic melanoma has shown no evidence in metastatic OM. Our study aims at narrowing the gap in knowledge in the treatment of OM with IO. Methods: We conducted a retrospective cohort study of patients with metastatic OM treated during the period 2017-2021 at the University of Louisville. Patients aged 18 years or more with treatment-naïve metastatic (Stage IV) OM were included. Data was censored according to date of last recorded clinical follow up or death. The primary outcome of interest was overall survival (OS). Subgroup analysis was done to examine survival based on initial treatment with dual versus single checkpoint inhibition. After progression on initial therapy, patients previously on dual inhibition went on to receive single inhibition, and vice versa. Kaplan-Meier survival analyses were generated using all-cause mortality as the competing outcome event and log-rank testing to evaluate differences between groups with alpha set at 0.05 for significance. Results: A total of 21 patients with Stage IV OM were identified with 4 excluded due to lack of data. The majority were male (10/17) and median age was 66 years, ranging from 30 to 89 years. More than half (10/17) received dual checkpoint inhibition as initial IO, with ipilimumab and nivolumab. The remainder received pembrolizumab or Nivolumab monotherapy (7/17). IO was well tolerated with no treatment related mortality and incidence of immune-related adverse effects similar to cutaneous melanoma. The median follow-up time overall was 56 months using the reverse Kaplan-Meier method with a median OS of 15 months. Estimated 2-year OS was 41%. No significant difference was found between single and dual checkpoint inhibition as the initial treatment regimen. Conclusions: While IO has markedly improved survival in advanced melanomas, OM continues to have inferior survival. Consistent with the literature by Zimmer et al, survival in this cohort is better than that reported with ipilimumab monotherapy. The median survival of 15 months is consistent with that reported by Heppt et al in the German multicenter study. IO for Stage IV OM was well tolerated, resulting in median survival of 15 months and 2-year OS of 41%. There was no survival advantage to initial treatment with single versus dual checkpoint inhibition, allowing for crossover at progression. Further research with novel agents and enrollment in clinical trials are needed in ocular melanoma.
A novel virus-like drug conjugate (VDC) in combination with immune checkpoint inhibitors for the treatment of primary tumors and distant metastasis.
Authors: Ruben Victor Huis in 't Veld, Sen Ma, Rhonda Kines, Anneli Savinainen, Cadmus Collins Rich, Ferry Ossendorp, Martine Jager
Journal: Journal of Clinical Oncology (2022)

e14544 Background: Although there has been great progress in the early diagnosis of choroidal melanoma, metastases remain the leading cause of cancer-related death. Therefore, improving the treatment efficacy against metastases is essential to enhance patient survival. A new targeted therapy, the virus-like drug conjugate (VDC) AU-011 (belzupacap sarotalocan), is currently in clinical development to treat early-stage choroidal melanoma with an intra-ocular administration followed by near-infrared (NIR) light activation using a photodynamic therapy (PDT) laser. Murine experiments have shown that AU-011 enhances immune checkpoint inhibition (ICI) and protects against tumor rechallenge. Methods: We investigated whether this combination therapy had an effect not only on primary tumors but also on distant, untreated tumors, as a model for treating metastatic cancer by abscopal immune effects and compared the efficacy of combining AU-011 with several ICI antibodies. Results: In vitro, AU-011 treatment induced a preferential cytotoxicity in cancer over antigen presenting cells, confirming the tumor-targeting of AU-011. AU-011 treatment induced immunogenic cell death in several murine cancer cell lines through the release and exposure of damage-associated molecular patterns (DAMPs), resulting in the maturation of dendritic cells. Furthermore, AU-011 in combination with ICI antibodies demonstrated greater efficacy than AU-011 alone, or ICI antibodies alone against established MC38 tumors in mice, resulting in complete tumor response in all treated animals for specific combinations. Finally, AU-011 and anti-PD-L1/ anti-LAG-3 antibody treatment was an optimal combination in an abscopal model of metastatic disease, inducing complete cures in approximately 75 % of animals. Conclusions: Based on our observations, we conclude that AU-011 treatment combined with immune checkpoint inhibition is effective against both primary tumors and distant metastases, and identify anti-PD-L1/ anti-LAG-3 as the most potent combination with AU-011. These data may support an investigation of AU-011 in this combination in future clinical trials.[Table: see text]
Extracellular mitochondria drive CD8 T cell dysfunction in trauma by upregulating CD39
Authors: Shilpa Tiwari-Heckler, Ghee Rye Lee, James Harbison, Carola Ledderose, Eva Csizmadia, David Melton, Quanzhi Zhang, Wolfgang Junger, Guanqing Chen, Carl J Hauser, Leo E Otterbein, Maria Serena Longhi, Simon Christopher Robson
Journal: Thorax (2022)

Rationale The increased mortality and morbidity seen in critically injured patients appears associated with systemic inflammatory response syndrome (SIRS) and immune dysfunction, which ultimately predisposes to infection. Mitochondria released by injury could generate danger molecules, for example, ATP, which in turn would be rapidly scavenged by ectonucleotidases, expressed on regulatory immune cells. Objective To determine the association between circulating mitochondria, purinergic signalling and immune dysfunction after trauma. Methods We tested the impact of hepatocyte-derived free mitochondria on blood-derived and lung-derived CD8 T cells in vitro and in experimental mouse models in vivo. In parallel, immune phenotypic analyses were conducted on blood-derived CD8 T cells obtained from trauma patients. Results Isolated intact mitochondria are functional and generate ATP ex vivo. Extracellular mitochondria perturb CD8 + T cells in co-culture, inducing select features of immune exhaustion in vitro. These effects are modulated by scavenging ATP, modelled by addition of apyrase in vitro. Injection of intact mitochondria into recipient mice markedly upregulates the ectonucleotidase CD39, and other immune checkpoint markers in circulating CD8 + T cells. We note that mice injected with mitochondria, prior to instilling bacteria into the lung, exhibit more severe lung injury, characterised by elevated neutrophil influx and by changes in CD8 + T cell cytotoxic capacity. Importantly, the development of SIRS in injured humans, is likewise associated with disordered purinergic signalling and CD8 T cell dysfunction. Conclusion These studies in experimental models and in a cohort of trauma patients reveal important associations between extracellular mitochondria, aberrant purinergic signalling and immune dysfunction. These pathogenic factors with immune exhaustion are linked to SIRS and could be targeted therapeutically.
EGFR mutations in lung carcinomas: Mutation profile and survival analysis.
Authors: Narayanankutty Edavalath Warrier, Dilip Harindran Vallathol, Uma V Sankar, Sameer Salahuddin, Sreedharan P. S., Prasanth V. Parameswaran, Sajeevan K V
Journal: Journal of Clinical Oncology (2022)

e20518 Background: Epidermal growth factor receptor (EGFR) mutation have been demonstrated to be both predictive and prognostic for patients with metastatic lung cancer. The administration of EGFR tyrosine kinase inhibitors (TKIs) has improved survival in this group of patients. Several generations of EGFR TKIs are currently available. The EGFR mutations have been divided into common and rare. The common mutations include Exon 19 deletion and Exon 21 L858R mutations and rest are grouped as rare. The presence of visceral metastasis in the brain and liver are usually portends a poor prognosis. Methods: We conducted a retrospective analysis of lung cancer patients who attended our hospital outpatient department from 2017 to 2021. The prevalence, demographics and clinical profile of EGFR common and rare mutations were studied using descriptive statistics. Survival of EGFR mutated patients was plotted using Kaplan Meier plots. SPSS was used for statistical analysis. Results: The prevalence of EGFR mutation among metastatic lung cancer was 14.10% (161/1148). The median age of the group was 60 years (23- 104 years). Smokers with EGFR mutations were 11.8% (n = 19). Male to Female ratios was 76:85 (47.2% and 52.8%). Three patients with squamous cell carcinoma exhibited EGFR mutation. Most common EGFR TKI used was Gefitnib. Osimertinib was used in 13 patients (1.4%). The percentage of common mutations were 85.75% (N = 132) and rare mutations were 14.3% (n = 22). The type of mutations could not be identified in 10 patients. The percentage of patients with exon 19 deletion were 63% (n = 97) and L858R were 24.7% (n = 38). Visceral metastasis (brain and liver) was seen in 47 patients (n = 29.2%). Brain progression was seen in 32 patients (n = 19.9%). The survival of patients with EGFR exon 19 deletion and L858R mutation was 16.36 + 8.97 months and 15.97+ 10.93 months, Survival among patients with common mutation was 16.20 + 9.57 months and among rare mutation was 13.43 + 12.19 months. Median Survival period of patients with visceral metastasis was 12 months (0 to 38 months). Conclusions: In our retrospective study, there was no significant difference between survival among common and rare EGFR mutations.
A prospective blinded validation of the rapid prostate cancer risk calculator for patients following initial multiparametric magnetic resonance imaging
Authors: E.J. Bass, M. Bertonelli Tanaka, M.J. Connor, U. Walters, D. Eldred-Evans, P. Sarkar, F. Hosking-Jervis, H. Bhola-Stewart, E. Pegers, L. Powell, D. Leelamany, K. Wong, S. Ahmad, H. Tam, H. Qazi, S. Gordon, D. Hrouda, S. Mccracken, M. Winkler, H.U. Ahmed
Journal: European Urology (2022)